NCT05217069

FOLFIRI + Cetuximab + Avelumab RAS Wild-type CRC

Avelumab Added to FOLFIRI Plus Cetuximab Followed by Avelumab Maintenance in Patients With Previously Untreated RAS Wild-type Colorectal Cancer. The Phase II FIRE-6 Study

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 57 (actual)
• Sponsor: Ludwig-Maximilians - University of Munich · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Within the proposed single arm multicenter phase-II trial it is intended to investigate the feasi-bility of adding Avelumab to FOLFIRI plus Cetuximab after 4 cycles (2 months) of treatment with FOLFIRI plus Cetuximab. After 4 more cycles of FOLFIRI plus Cetuximab plus Avelumab the treatment will be de-escalated to Avelumab as a maintenance concept until progression of the disease according to RECIST 1.1 has occurred.

Detailed description

After 4-6 months of doublet chemotherapy a de-escalation to a less toxic regimen is needed for most of the patient with mCRC. The addition of Avelumab to a cytotoxic chemotherapy regimen with FOLFIRI plus cetuximab followed by Avelumab maintenance has not been in-vestigated so far. It is known that FOLFIRI plus cetuximab leads to necrosis and therefore tumor antigens that usually are not presented to the host immune system become recogniza-ble. This effect of a triggered immune system after induction treatment with chemotherapy is currently investigated in other trials. The ongoing IMPALA trial is testing the toll-like receptor (TLR)-9 agonist MGN1703 as maintenance treatment in patients that have responded to an induction doublet chemothera-py. This effect may be enhanced by the fact that Cetuximab in Combination with 5-FU and Irinotecan triggers immunogenic cell death. The lately published data from the interim analysis of the PACIFIC trial using the anti-PD L1 antibody durvalumab after chemoradiation in stage II non-small cell lung cancer (NSCLC) proofed the concept of an anti-PD L1 antibody as a maintenance treatment after chemoradi-ation. Durvalumab prolonged PFS significantly (HR 0.52, p\<0.001). The study is not limited to MSI-h and should be able to demonstrate Avelumab efficacy in MSS tumors. The lately presented data on the use of atezolizumab plus cobimetinib (NCT01988896) in in heavily pretreated MSS mCRC patients showed a 12-month OS rate of 43% which was higher than the 24% seen for Regorafenib in the pivotal CORECT trial. Therefore it is worthwhile to test this concept in MSS mCRC. Furthermore part of the cetuximab effect can be attributed to ADCC (antibody derived cellu-lar cyctotoxicity) with again leads to necrosis of tumor cells and the release of antigens. Both effects together may be able to present enough tumor-neo-antigens. To boost the effect, Avelumab is able to inhibit the PD-1 derived inhibition of cytolysis and other tumor cells within the body may be attacked by the immune system which leads to an anti-tumor effect repre-sented by a prolonged PFS and finally OS of the patients.

Conditions

• Treatment Related Cancer

Interventions

Type	Name	Description
DRUG	5-FU	400 mg/m2 (i.v. bolus) 2400 mg/m2 (i.v. 46h)
DRUG	Folinic Acid	400mg/m2
DRUG	Irinotecan	180 mg/m2
DRUG	Cetuximab	400 mg/m2 i.v. 120min initial dose 250 mg/m2 i.v. 60min q 1w
DRUG	Avelumab	10mg/kg IV (day 1 q2w)

Timeline

• Start date: 2019-09-27
• Primary completion: 2023-09-01
• Completion: 2023-10-18
• First posted: 2022-02-01
• Last updated: 2025-04-16

Locations

1 site across 1 country: Germany